2116. Efficacy of CD388, a Novel Drug Fc-Conjugate (DFC), is Driven by the Small Molecule Neuraminidase Inhibitor (NAI)

Abstract Background Influenza prevention remains a significant public health concern that is still not adequately addressed by vaccines or current therapeutic options. Cidara has developed CD388, a multivalent conjugate of a dimeric NAI with a proprietary hIgG1 Fc domain engineered for extended half-life. CD388 is in clinical development (NCT05285137 and NCT05523089) for the prevention of seasonal influenza A and B. Herein we analyze the contribution of Fc-mediated immune effector function to CD388 efficacy. Methods CD388, Fc engineered to extend PK, and closely related Fc modified analogues (immune-active ‘IA’ or immune-silent ‘IS’) were generated. CD388-IA can engage Fc gamma receptors (FcγRs) whereas IS fails to engage FcγRs required to trigger Fc-mediated immune effector functions (e.g. antibody-dependent cellular cytotoxicity). Efficacy studies were conducted in BALB/c WT or Fcer1g-/- mice. The Fcer1g-/- mice are deficient in activating FcγRs thereby excluding contribution of Fc-mediated immunity to efficacy. After lethal challenge with influenza A virus, CD388 or analogues were administered subcutaneously or intramuscularly two hours post-infection. Animals were monitored daily for 14 days or longer for survival (< 20% BW loss). For viral burden quantification, lungs were harvested on day 4 post-infection and viral titers were determined by plaque assay. Results CD388-IA and -IS at comparable drug to antibody ratios (DARs) of 4.5±0.5 (used in the clinical candidate) demonstrated comparable protection (Figure 1) and comparable dose-dependent viral burden and cytokine reduction in a lethal mouse model (Table 1). Additionally, the CD388-IA analogue at DAR 4.7 was protective in Fcer1g-/- mice at the same doses required for protection in WT mice. However, a CD388-IA analogue at low DAR of 1, that has reduced antiviral activity, demonstrated improved efficacy in WT mice as compared to KO mice (Figure 2).Figure 1. Efficacy of CD388-IA and CD388-IS against A/PR/8/1934 (H1N1) in a lethal mouse model in BALB/c WT mice showing survival (A) and body weight (B)Figure 2. Efficacy of CD388-IA at DAR 1 or 4.7 against A/PR/8/1934 (H1N1) in a lethal mouse model in BALB/c WT (B, D) or KO (A, C) miceTable 1. Viral burden reduction and cytokine levels in fold-change versus uninfected control for IL-6, MIP-1□ and MCP-1 on day 4 post-infection in a lethal influenza A/H1N1 mouse model. Conclusion These data combined demonstrate that the efficacy of CD388 at DAR 4.5±0.5 is driven predominantly by the intrinsic antiviral activity of the small molecule NAI and is independent of the contribution of Fc-mediated effector functions. Disclosures Simon Döhrmann, PhD, Cidara Therapeutics: Stocks/Bonds James Levin, PhD, Cidara Therapeutics: Stocks/Bonds Elizabeth Abelovski, B.S., Cidara Therapeutics: Ownership Interest Amanda Almaguer, Bachelors, Cidara Therapeutics: Stocks/Bonds Rajvir Grewal, n/a, Cidara Therapeutics: Ownership Interest Karin Amundson, BSc, Cidara Therapeutics: Stocks/Bonds Joanne Fortier, BSc, Cidara Therapeutics: Stocks/Bonds Thanh Lam, PhD, Cidara Therapeutics: Stocks/Bonds Thomas P. Brady, Ph.D., Cidara Therapeutics: Stocks/Bonds Allen Borchardt, PhD, Cidara Therapeutics: Stocks/Bonds Jason N. Cole, Ph.D., Cidara Therapeutics: Stocks/Bonds Leslie W. Tari, Ph.D., Cidara Therapeutics: Stocks/Bonds

Session: 226.Antimicrobial Novel Agents Saturday, October 14, 2023: 12:15 PM Background.Influenza prevention remains a significant public health concern that is still not adequately addressed by vaccines or current therapeutic options.Cidara has developed CD388, a multivalent conjugate of a dimeric NAI with a proprietary hIgG1 Fc domain engineered for extended half-life.CD388 is in clinical development (NCT05285137 and NCT05523089) for the prevention of seasonal influenza A and B. Herein we analyze the contribution of Fc-mediated immune effector function to CD388 efficacy.
Methods.CD388, Fc engineered to extend PK, and closely related Fc modified analogues (immune-active 'IA' or immune-silent 'IS') were generated.CD388-IA can engage Fc gamma receptors (FcγRs) whereas IS fails to engage FcγRs required to trigger Fc-mediated immune effector functions (e.g.antibodydependent cellular cytotoxicity).Efficacy studies were conducted in BALB/c WT or Fcer1g -/-mice.The Fcer1g -/-mice are deficient in activating FcγRs thereby excluding contribution of Fc-mediated immunity to efficacy.After lethal challenge with influenza A virus, CD388 or analogues were administered subcutaneously or intramuscularly two hours post-infection.Animals were monitored daily for 14 days or longer for survival (< 20% BW loss).For viral burden quantification, lungs were harvested on day 4 post-infection and viral titers were determined by plaque assay.
Results.CD388-IA and -IS at comparable drug to antibody ratios (DARs) of 4.5±0.5 (used in the clinical candidate) demonstrated comparable protection (Figure 1) and comparable dose-dependent viral burden and cytokine reduction in a lethal mouse model (Table 1).Additionally, the CD388-IA analogue at DAR 4.7 was protective in Fcer1g -/-mice at the same doses required for protection in WT mice.However, a CD388-IA analogue at low DAR of 1, that has reduced antiviral activity, demonstrated improved efficacy in WT mice as compared to KO mice (Figure 2).Table 1.Viral burden reduction and cytokine levels in fold-change versus uninfected control for IL-6, MIP-1□ and MCP-1 on day 4 post-infection in a lethal influenza A/H1N1 mouse model.

Conclusion.
These data combined demonstrate that the efficacy of CD388 at DAR 4.5±0.5 is driven predominantly by the intrinsic antiviral activity of the small molecule NAI and is independent of the contribution of Fc-mediated effector functions.
50/90 values, 256/512 mg/L using the 50% inhibition reading criterion).There was no evidence that TAU activity was affected by isolate source or clade.Based on these data, catheter lock solutions containing the broad-spectrum antimicrobial TAU at 13,500 mg/L have the potential to prevent CRBSI caused by CA.
1 University of New Mexico College of Pharmacy, Albuquerque, New Mexico 2 Anti-infective Research Lab, Wayne State University, Detroit, Michigan 3 Wayne State University, Detroit, Michigan 4 University of Indiana Health, Bloomington, Indiana 5 Indiana University Health, Bloomington, Indiana 6 Memorial Hospital West, Pembroke Pines, Florida 7 Orlando Health, Orlando, Florida 8 Cleveland Clinic, Cleveland, Ohio 9 Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan 10 Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan 1 IHMA, Schaumburg, Illinois 2 Pfizer, Inc., Kirkland, Manitoba, Canada 90 values for ATM-AVI of 0.12 µg/ml (pediatric isolates) and 0.25 µg/ml (adult isolates) were observed.Against all Eba isolates, ≤8 µg/ml of ATM-AVI was sufficient to inhibit 99.9% of both pediatric and adult isolates, whereas only 68.0% (pediatric) and 71.9% (adult) of these isolates were susceptible to ATM alone (table).Among isolates that screened positive for an MBL, MIC 90 values for ATM-AVI were 0.5 µg/ml (pediatric) and 1 µg/ml (adult) and ATM-AVI inhibited 100% (pediatric) and 99.1% (adult) at concentrations ≤8 µg/ml.In contrast, only 16.1% (pediatric) and 17.9% (adult) of MBL-positive isolates were susceptible to ATM alone.90 values, ATM-AVI demonstrated potent in vitro activity against Eba isolated both from pediatric and adult patients.Avibactam's ability to potentiate ATM against MBL-positive isolates warrants its continued development.

Figure 1 .
Figure 1.Efficacy of CD388-IA and CD388-IS against A/PR/8/1934 (H1N1) in a lethal mouse model in BALB/c WT mice showing survival (A) and body weight (B)